Topical analgesic compositions containing aliphatic polyamines and methods of using same

ABSTRACT

A method for producing local analgesia in a subject having a site of local discomfort. A composition to be administered includes an aliphatic polyamine. The polyamine can be an alkylamine. Particular amines include putrescine, spermine, spermidine and cadaverine. The composition can also include urea and/or lidocaine.

FIELD OF INVENTION

[0001] This invention relates to topical analgesia and to methods andcompositions, etc. for treating pain or discomfort in a mammal.

BACKGROUND OF THE INVENTION

[0002] Pain occurs frequently and is a common symptom for which patientsseek medical assistance. Defined as an unpleasant subjective sensationwhich results from a noxious stimulus, pain alerts the body to possibleor actual danger, such as during disease or physical trauma. The needsof a patient in temporary or chronic pain include comfort, freedom fromadverse reactions, the ability to perform the functional activities ofdaily living, psychological reassurance, and a satisfying quality oflife.

[0003] The pathological mechanism of pain and its perception by thesubject remains an area of considerable research. Despite a lack ofcomprehensive understanding of the many dimensions of pain, many agentshave been developed to be effective in its treatment.

[0004] Analgesics are a broad class of agents developed for use in thetreatment and management of pain. Major classes of analgesic compoundsinclude analgesic-antipyretic compounds which are compounds thatalleviate pain and/or reduce fever, such as salicylates and relatedcompounds, and narcotic analgesics or opiates, which alleviate painand/or induce sleep. The analgesic potency of a compound generallycorrelates with its solubility in lipids. It is believed that analgesiaoccurs when lipid structures in neurosensory cell membranes aredisrupted by a dissolved analgesic agent.

[0005] Analgesics can be broadly divided into two classes of agents,i.e.: systemic analgesics and topical analgesics. Compounds displayinganalgesic properties are not necessarily effective as both systemic andtopical analgesics. Systemic analgesics, which are typically swallowedor injected, are frequently prescribed for the treatment of pain. Themost common treatment for chronic pain is with the use of thesalicylate-like agents known as nonsteroidal anti-inflammatory drugs(NSAIDs). Unfortunately, side effects can be associated with the use ofthese drugs, including gastrointestinal and renal abnormalities.

[0006] Unlike systemic agents that are swallowed or injected, topicalanalgesics, typically available in the form of salves, creams, ointmentsand rubs, work only on the area they are rubbed into, reducing oreliminating the risk of systemic side effects. Topical analgesics may beappropriate for subjects with muscle ache or mild pain that affects onlya few joints. They may also provide relief for subjects whose oralmedications alone fail to reduce their pain to manageable levels, suchas, for example, from arthritic pain. They may also provide means ofprophylaxis of pain. However, topical administration of an analgesicrequires that the analgesic be able to reach the sensory receptorsimplicated in pain. In particular, topical analgesics for use on theskin must first be able to penetrate dense stratum corneum, keratinizedcomeocytes and the restrictive epidermal cell layer barrier of the skinsurface.

[0007] Different types of agents have been found to be effective astopical analgesics. Most common topical analgesics include one or moreof three commonly used analgesic agents which can be broadly classifiedas counter-irritants, salicylates, and caspaicin. Counter-irritantsstimulate nerve endings distracting the brain's attention frommuscoskeletal pain, and encompass such substances as menthol, camphor,etc. Salicylates inhibit prostaglandins which contribute to pain andinflammation. Such compounds are often found to act as systemicanalgesics as well. Caspaicin is a naturally occurring drug which worksby depleting a neurotransmitter substance that is implicated in sendingpain messages to the brain. These active agents are usually applied ascomponents in compositions to an area in need of analgesia. Thesecompositions often include agents that aid in the transcutaneousdelivery of the analgesic agent to the sensory receptors. As well,lidocaine, lignocaine, xylocaine, benzocaine, tetracine, prilocaine,bupivacaine, and the like, are used as topical analgesics. However,their toxicities are well established and great care must be taken toensure that the dosage of these agents is not exceeded to toxic levels.Toxic effects include formation of sulfhemoglobin and methhemoglobin, aswell as effects on the central nervous system.

[0008] Thus, the development of topical analgesics for the management ofpain which provide fast and effective relief or reduction of pain, yetexhibit reduced side effects, is an ongoing need.

SUMMARY OF THE INVENTION

[0009] The present invention involves alleviation of pain or discomfortof a subject by aliphatic polyamines that produce an analgesic effect intheir topical administration to the subject. An analgesic is an agentused in the treatment of pain.

[0010] One embodiment of the invention is a method for producing localanalgesia in a subject having a site of local discomfort. The methodincludes topically administering an effective amount of an aliphaticpolyamine to the site.

[0011] In another embodiment, the invention is a method for producingrelief in a subject having a site subject of nociceptive stimulation.The method includes topically administering an effective amount of analiphatic polyamine to the site.

[0012] The polyamine can be in the form of a free base or it can be apharmaceutically acceptable salt of a polyamine, or it can be a mixtureof the two. Of course, the form selected would be compatible with theuse to which the polyamine is to be put. For application to human skin,the free base or salt(s) would be compatible for use with human skin.Salts that produce deleterious effects would generally be avoided.

[0013] In particular embodiments, the polyamine has up to fifteen carbonatoms. Certain preferred polyamines are limited to four amino groups,while certain embodiments have three amino groups and some have only twoamino groups. In certain embodiments, the polyamine(s) is saturated. Incertain embodiments, the polyamine is non-cyclic. In certainembodiments, the polyamine has only ten carbon atoms, but it may havemore, or less, particularly, nine, or eight, or seven, or six or fivecarbon atoms. Particular polyamines of the invention are putrescine,cadaverine, spermine and/or spermidine. Spermidine is the “doublet” ofputrescine and spermine is the “triplet.” Preferably, the polyamine hasat least four carbon atoms.

[0014] In compositions of the invention, the polyamine can make upbetween 0.1 and 10 weight percent of the composition that is to beadministered to the site. In other embodiments, between 0.2 and 9percent, or between 0.3 and 8 percent, or between 0.4 and 7 percent, orbetween 0.5 and 6 percent or between 0.6 and 5 percent, or between 0.7and 5 percent, or between 0.8 and 5 percent, or between 1 and 4 percentor between 1 and 3 percent, or between 1 and 2 percent. The polyaminecan thus constitute about 0.1, 0.2, 0.3, 0.4, 0.5, 0.8, 1.0, 1.3, 1.5,1.8, 2.0, 2.3, 2.5, 2.8, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6, 7, 8, 9 or 10weight percent of the composition that is to be administered to thesite.

[0015] The site of topical application would usually be the epidermis,the outer skin layer of the subject. The subject is usually human, butcould be another mammal, such as a horse or dog, for example.

[0016] A composition of the invention preferably includes a chaotropicagent, or penetration agent, which enhances delivery of the analgesiccomponent into lower layers of the skin aiding its delivery to the siteof action. The agent can be urea, or it can be oleic acid, for example,or it can be a combination of such agents.

[0017] Urea has been found to be particularly useful in this regard.Preferred embodiment compositions include urea in a concentration of atleast 10 percent, more preferably in a concentration of at least 15percent by weight of the composition. Usually, the concentration of ureawould be no more than 40 percent. The concentration of urea could beabout 10, or about 15 or about 20, or about 25 or about 30 or about 35or about 40 percent by weight of the total weight of the composition.

[0018] In certain embodiments of the invention, the composition is acream, or a spray, or an ointment, or a gel or a lotion, for applicationto a subject's skin.

[0019] A preferred mode of administration is with the use of a patch. Apatch can be mounted to the site to be treated. The patch has thepolyamine incorporate thereinto at the site such that the polyamine istransferred from the patch to the site.

[0020] In using such a patch, release of the polyamine from the patchcan be controlled to produce the analgesic effect over a period of time.The period of time can be, for example, up to about one week, or betweenabout one hour and one week, or between one hour and six days, orbetween six hours and five days, or between six hours and four days, orbetween twenty-four hours and three days, or between one day and twodays.

[0021] In certain preferred embodiments, the composition can includebeta 1,3-D glucan.

[0022] In a particularly preferred embodiment, the composition includeslidocaine, a known local anaesthetic.

[0023] Topical sites treatable through the present invention includethose where discomfort is the result of a sports injury, a physicalassault, arthritis, rheumatism, headache, shingles, surgical pain, or acombination of any of the foregoing.

[0024] The source of discomfort can be one of non-pathological etiology.

[0025] The invention can be used in a subject suffering fromfibromyalgia.

[0026] In a particular embodiment, the site of treatment is free ofextracellular wound scar skin tissue and/or the site is free of a woundundergoing healing of the skin.

[0027] The invention includes manufacture of a composition of theinvention, and particularly those for use according to any method of theinvention, for example, in topically administering the composition to anaffected site.

[0028] In preferred embodiment compositions, the polyamine of theinvention is admixed with a suitable pharmaceutically-acceptable diluentor carrier.

[0029] Several properties of putrescine are known that make it suitablefor use as a topical analgesic, including that it is a naturallyoccurring substance which is a normal metabolite in cells, it is aubiquitous component in foods, and it has been shown to have a very lowtoxicity when administered via many routes including orally,intravenously, intraperitoneally, and intramuscularly.

[0030] In a preferred embodiment, the aliphatic polyamine is putrescinedihydrochloride.

[0031] In another aspect, the invention relates to a pharmaceuticalcomposition in dosage unit form suitable for topical administration to amammal for effecting analgesia in a mammal desiring such analgesia,which comprises an effective amount of an aliphatic polyamine or apharmaceutically-acceptable salt thereof, in admixture with a suitablepharmaceutically acceptable diluent or carrier.

[0032] In another aspect, the invention provides a commercial packagecontaining as an active pharmaceutical ingredient an aliphatic alkylpolyamine or a pharmaceutically-acceptable salt thereof, together withinstructions for the use thereof for inducing analgesia in a mammal.

[0033] In another aspect, the invention provides a process for preparingan agent for effecting topical analgesia in a mammal, in ready-to-usedrug form for the treatment of pain, characterized in that an aliphaticpolyamine or a pharmaceutically acceptable salt thereof is used as anactive ingredient in the agent.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENT

[0034] For purposes of clarity, the following terms and phrases usedthroughout this specification and the appended claims are defined in themanner set forth directly below.

[0035] The term “analgesia” as used herein means the reduction, orabsence, of sensibility to pain, designating particularly the relief ofpain without consciousness.

[0036] The term “malady” generally refers to an illness or disease.

[0037] The term “composition” is meant to embrace both a singlesubstance and a mixture of substances.

[0038] The term “polyamine” as used herein means one or more than oneamino group.

[0039] The term “amino” as used herein means —NH₂.

[0040] The term “aliphatic” means acyclic or cyclic, saturated orunsaturated carbon compounds, excluding aromatic compounds. Saturatedcarbon compounds include hydrocarbons having from one to twenty carbonatoms, within which includes from four to eleven carbon atoms, andfurther which includes from four to five carbons, and which can bestraight or branched chain. Representatives of such groups are n-butyl,n-pentyl, n-propyl, sec-butyl, isobutyl, etc.

[0041] The term “alkyl” as employed herein means a saturated hydrocarbonhaving from one to twenty carbon atoms, within which includes from fourto eleven carbon atoms, and further which includes from four to fivecarbons, and which can be straight or branched chain. Representatives ofsuch groups are n-butyl, n-pentyl, n-propyl, sec-butyl, isobutyl, etc.

[0042] The term “pharmaceutically-acceptable” as employed herein meansthose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problems or complication,commensurate with a reasonable benefit/risk ratio.

[0043] The term “pharmaceutically-acceptable salts” in this respectrefers to the relatively-non-toxic, inorganic and organic addition saltsof compounds of the present invention. Representative salts include thehydrochloride, hydrobromide, sulphate, phosphate, nitrate, acetate (seefor example, S. M. Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19 (1977)).

[0044] The term “chaotropic agent” as employed herein means an agentthat breaks up dense macromolecular and lipid-rich domains. Someexamples of materials that can serve as chaotropic agents include urea,substitutes ureas, amides and dimethyl sulphoxide.

[0045] The phrase “pharmaceutically-acceptable carrier” as employedherein means a pharmaceutically-acceptable material, composition orvehicle, as defined directly above, such as a liquid or solid filler,diluent, excipient, solvent, involved in carrying or transporting achemical compound or pharmaceutical agent from one portion of the bodyto another portion of the body. Some examples of materials that canserve as carriers include: sugars, such as lactose and glucose;starches, such as corn starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose and cellulose acetate; malt; gelatin;talc; oils, such as olive oil; glycols, such as propylene glycol;polyols, such as glycerin, polyethylene glycol; esters, such as ethyloleate; agar; buffering agents, such as magnesium hydroxide; water;ethyl alcohol; and other non-toxic compatible substances employed inpharmaceutical formulations.

[0046] The present invention includes a use of an aliphatic polyamine asa topical analgesic and topical analgesic compositions containing analiphatic alkyl polyamine.

[0047] A number of the aliphatic alkyl polyamine compounds useful in thecomposition and methods of the present invention are known in thechemical art. The amine group contained by the aliphatic polyamines maybe either primary or secondary and may be located either in a terminalposition, within the alkane chain, or both. In a preferred embodiment,the preferred aliphatic polyamines useful in the compositions andmethods of the present invention are spermidine (4,4′-iminobisbutylamine), spermine (N,N′-Bis(3-aminopropyl)-1,4-butane-diamine),cadaverine (1,5-pentanediamine) and putrescine (1,4-diaminobutane).Details of the synthetic preparation of a number of the aliphaticpolyamines utilizable in the compositions and methods of the presentinvention may be found in Beilsteins Handbuch Der Organischen Chemie.The Merck Index, 11th edition, also references many of the preferredcompounds of this invention.

[0048] The free base form of the aliphatic polyamines utilized in thepresent invention may be conveniently converted to the correspondingacid addition salt by contacting a solution of the free base with theappropriate acid. Particularly preferred salts are the acid additionsalts formed with hydrochloric and sulfuric acids, e.g., hydrochlorideand sulfate.

[0049] The compositions of the present invention comprise one or more ofthe above-mentioned aliphatic polyamines in a sufficient quantitytogether with a suitable pharmaceutical carrier to induce topicalanalgesia. The aliphatic polyamnines act as analgesic agents. Asufficient quantity is defined as the amount of compound necessary toinduce analgesia. In the usual course of therapy, the aliphaticpolyamine is incorporated into an acceptable vehicle to form acomposition for topical administration to the area sensing pain and,thus, requiring analgesia.

[0050] The dosage levels of the aliphatic polyamine in thepharmaceutical compositions of this invention may be varied so as toobtain an amount of the active ingredient that is effective to achievethe desired therapeutic response for a particular use, or compositionwithout being toxic to the subject. In a preferred embodiment, theamount is 1.0 weight percent. In another embodiment, the amount is 0.8weight percent. In yet another preferred embodiment, the amount is 2.0weight percent. In other embodiments, the percentage may be higher orlower. In a preferred embodiment, a concentration of putrescine at 0.8percent weight per volume of the composition in a eutectic base is usedfor inducing analgesia to an area of the skin of a human. A topicalcomposition containing 0.8 percent weight per volume of putrescine in aeutectic base for the treatment of scar tissue is described in U.S. Pat.No. 5,885,982. In general, such compositions are envisioned to containthe active ingredient in from about 0.005% to about 5% volume by weightof the total composition. The use of putrescine as a non-topical,systemic analgesic by intraperitoneal and intracerebroventricularinjection into rats at 200 to 400 mg/kg of body weight is known. See,Genedani et al., Life Sciences, 34, 2407-2412 (1984).

[0051] While it is might be possible for an aliphatic alkyl polyamine ofthe present invention to be administered in pure form, it is preferableto administer the compound as a topical pharmaceutical composition tofacilitate spreading over the area in need of analgesia. Compositionsfor topical application may be exemplified by ointments, creams,lotions, solutions, suspensions, aerosols, gels, dusting powder, andimpregnated bandages and dressings. Such compositions would normally bebased upon standard carriers such as pharmaceutically acceptablevegetable oils and gelatins, gums and petrolatum. Other ingredients ofthe composition of the invention may be preservatives, coloring,thickening, suspending, disbursing, emulsifiing, swelling, stabilizingand buffering agents, fats, oils, waxes, paraffins, starch, polyethyleneglycols, silicones, bentonites, talc, zinc oxide, etc., as required bythe specific formulation. In a preferred embodiment, the pharmaceuticalcarrier is a eutectic base (Glaxo Canada Ltd., Toronto, Ont.).

[0052] A polyamine of the invention can also be incorporated intopatches or so-called transdermal therapeutic systems (TTS). From thesethe active substance components act on the skin over a defined area ofthe body surface in occlusive manner at a controlled release rate andare appropriately brought to transdermal absorption.

[0053] It is well known that the rate of transport of some substancesthrough the skin depends on the polar-nonpolar nature of the substance,size of the substance, hydration of the skin, blood supply, andmodification of the stratum corneum by chemicals. Thus, in a preferredembodiment, a chaotropic agent is present in the composition. In apreferred embodiment, the chaotropic agent is urea. In yet anotherpreferred embodiment, urea is present at about fifteen weight percent ofthe composition. In yet another preferred embodiment, urea is presentfrom between about one and twenty weight percent of the composition.Such chaotropic agents can facilitate penetration of the analgesic agentinto the skin as they break up dense macromolecular domains of fibrousand globular proteins.

[0054] In another preferred embodiment, a beta-1,3-glucan can be addedto promote healing in the area of the subject requiring analgesia shouldthe area also require healing. In another embodiment, a beta-1,3-glucanis present at about six to eight percent by weight of the totalcomposition. Beta-1,3-glucans may be derived from, among other things,purified yeast cell walls, and are well known to stimulate theimmunosystem.

[0055] Repeated use of the analgesic compositions of the presentinvention is envisaged, the length of time of use being dependent uponthe length of time that is required until analgesia is effected. Aswell, the dosage size and frequency of administration can vary dependingupon the nature and intensity of the pain. The exact dosage to beadministered and length of time of use with a subject will, of course,be dependent upon, among other factors, the particular compositionsemployed, and the disease or injury being treated.

[0056] A variety of uses have been tried for the analgesic compositionsof the present invention invention, for example: headache, frontalheadache, arthritis, anti-nociception, rheumatism, shingles,post-herpetic neuralgia, joint pain (in the arm, leg, shoulder, toe,ankle, etc. for example), post surgical pain, tenderness in breasts,burns, tense muscles, chest pain, injuries, sports injuries (forexample, shin splints, pulled muscles, sprain, etc.), repetitive stressinjuries including tennis elbow, fibromyalgia, rotator cuff pain,muscoskeletal pain. In a preferred embodiment, the composition of theinvention is applied to an area of a shoulder requiring analgesia due topain originating from the rotator cuff and includes putrescine at about2 percent by weight of the composition.

[0057] The following examples describe in detail compositionsillustrative of the present invention and methods for their utilization.It will be apparent to those skilled in the art that many modifications,both of materials and methods may be practiced without departing fromthe purpose and intent of the disclosure. All components arecommercially available.

EXAMPLE 1

[0058] Topical cream composition according to the present invention isprepared from the following components: Component Percent by weightdeionized water 55 urea USP 15 glycerin 6 triethanolamine 99% 4 GMS/PEG100 stearate 3.5 emulsifying wax NF (polawax) 3 hydrogenatedpolyisobutylene 3 lactic acid 3 cetyl alcohol (hexadecyl alcohol) 2.5putrescine 1 malic acid 3 silk protein (amino acid) 1 imidazolidinylurea 0.4 methyl paraben 0.2 carbomer 934P 0.1 propyl paraben 0.1 tetrasodium EDTA 0.1

EXAMPLE 2

[0059] Topical balm composition according to the present invention isprepared from the following components: Component Percent by weightBeeswax 5 Cetyl alcohol 3 GMS/PEG 100 stearate 6 imidazolidinyl urea 0.4Lactic acid 3 Lanolin 4 Malic acid 3 Methyl paraben 0.2 Mineral oil 5Propyl paraben 0.1 Putrescine 1 Silk protein (amino acid) 2 Tetra sodiumEDTA 0.1 Triethanolamine 0.25 Urea USP 25 Deionized water 41.95

EXAMPLE 3

[0060] Topical lotion composition according to the present invention isprepared from the following components: Component Percent by weightCarbomer 941 0.1 Cetyl alcohol 2 Emulsifying wax NF (polawax) 1 GMS/PEG100 stearate 2.0 Hydrogenated polyisobutene 4.5 imidazolidinyl urea 0.4Isopropyl myristate 4 Lactic acid 3 Malic acid 2 Propylene glycol 5Putrescine 2 Quaternium 15 (Dow 200) 0.05 Silk protein 1 Tetra sodiumEDTA 0.1 Triethanolamine 99% 1.25 Urea USP 10 Deionized water 61.6

EXAMPLE 4

[0061] Topical lotion composition according to the present invention isprepared from the following components: Component Percent by weightallantoin 0.2 Carbomer 940 0.1 Cetyl alcohol 2 Dimethicone (Dow fluid350) 0.5 Emulsifying wax NF (polawax) 2 Glyceryl stearate 2 Hydrogenatedpolyisobutene 5 Imidazolidinyl urea 0.3 Isopropyl myristate 5 Methylparaben 0.2 Propyl paraben 0.1 Propylene glycol 5 Putrescine 1 Silkprotein (amino acid) 1 Tetra sodium EDTA 0.1 Triethanolamine 0.3Deionized water 75.2

EXAMPLE 5

[0062] Topical composition according to the present invention withlidocaine and putrescine present is prepared from the followingcomponents: Component Percent by weight Allantoin 0.2 Carbomer 940 0.4Carbowax PEG-400 5 Imidizolidyl urea 0.3 Lechithin 1 Lidocaine 4 Methylparaben 0.2 N-propyl alcohol 7 Oleic acid 1 Putrescine 2 Tetradecyltetrasodium EDTA 0.2 Triethanolamine 4.75 Urea USP 10 Deionized water63.95

EXAMPLE 6

[0063] Topical massage cream composition according to the presentinvention is prepared from the following components: Component Percentby weight Arnica oil 0.5 Calendula oil 0.5 Camphoracious 804 0.05 Cetylalcohol 2 Dimethicone (Dow fluid 350) 0.5 Glyceryl stearate 3 GMS/PEG100 stearate 5 Imidazolidynyl urea 0.4 Isopropyl palmitate 5 Lactic acid1.25 Menthol USP 0.05 Mineral oil, medium 15 Peppermint oil 0.05Propylene glycol 5 Putrescine 2 Quaternium 15 (Dow 200) 0.05 Silkprotein (amino aicd) 0.5 Sorbic acid 0.15 Triethanolamine 0.2 Urea USP 1Deionized water 57.8

EXAMPLE 7

[0064] Topical cream composition according to the present invention isprepared from the following components: Component Percent by weightPutrescine 0.8 Glaxo eutectic base 99.2

[0065] The putrescine is dissolved in deionized water in a one to oneratio before adding to the Glaxo base.

[0066] Feasibility studies

[0067] In order to assess the analgesic effects of the method of use ofthe compounds of the invention and the compositions of the presentinvention, studies have been conducted. In the following study, theeffect of the composition on a group of subjects in pain was evaluated.

[0068] Sixteen subjects experiencing pain were given a sample of thecomposition of Example 1 (the “Example 1” composition) and a sample ofthe composition of Example 1 that does not include the activeingredient, putrescine (the “placebo” composition). The subjects wereadvised to topically administer the compositions at different periods ofpain and to then rate the effectiveness of the two compositions. Painwas estimated by a ranking system from 0 to 5, wherein 0 was no effect,while 5 represented maximum perceived relief of pain. The data arepresented in Table I and show that the perceived pain decreased withapplication of the composition containing putrescine. As well, 15 out of16 subjects did not perceive a decrease in pain after application of theplacebo composition. TABLE 1 Number of subjects reporting the followingresponse Composition 0 1 2 3 4 5 Example 1 3 1 — — 4 8 Placebo 15 1 — —— —

[0069] Similarly, subjects experiencing pain were given a sample of thecomposition of Example 1 (the “Example 1” composition) and a sample ofthe composition of Example 1 that does not include the activeingredient, putrescine (the “placebo” composition). The subjects wereadvised to administer the compositions at different periods of pain andto then rate the effectiveness of the two compositions. Pain wasestimated by a ranking system from 0 to 5, wherein 0 was no effect,while 5 represented maximum perceived relief of pain. The data arepresented in Table 1 and show that the perceived pain decreased withapplication of the composition containing putrescine. TABLE 2 Rating ofRating of Subject No. Example 1 Placebo Type of pain 1 4 1 Arthriticpain in back 2 4 0 Pain in toe from sports injury 3 5 0 Stiffness inknee 4 1 0 Torn muscle in leg 5 0 0 Soreness from prior ankle injury 6 5— Sprained ankle 7 5 0 Pain in upper arm 8 0 0 Pain associated withcirculatory problems in the hands 9 5 0 Arthritic pain in toe 10 5 0Arthritic pain in hand 11 5 0 Muscle tightness in back 12 4 0 Headache13 5 0 Arthritic pain in toe 14 3 0 Rotator cuff pain 15 5 0 Headache 160 0 Burning sensation in foot 17 5 1 Arthritic pain in back and leg 18 50 Arthritic wrist 19 5 0 Frontal headache 20 3 1 Frontal headache

[0070] Tests were also conducted on twelve subjects suffering fromarthritis. Half of the subjects were a placebo for topicaladministration and the others were given the following composition:Component % w/w deionized water 46 urea 20 lactic acid 7.5 propyleneglycol 5 hydrogenated polyisobutene 4.5 isopropyl myristate 4 sodiumhydroxide 3.2 cetyl alcohol 2.5 peg 100 stearate 2 putrescine 2emulsifying wax 1.5 silk protein(amino acid) 1 imidazolidinyl urea 0.4allantion 0.1 carbomer 940 0.1 di sodium EDTA 0.1 quaternium 15 0.1

[0071] This composition contains 2% putrescine. The results aresummarized in Table 3. Three people who were given the placebo droppedout prior to completion of the study. TABLE 3 Relief Ranking 2%putrescine Analgesic Placebo Ranking 0 2 1 1 2 3 2 4 1 5 3

[0072] Tests were also conducted on people suffering from fibromyalgiato compare relief obtained with a topical composition containing 20percent triethanolamine salicylate (Bayer Myoflex) to theabove-indicated 2 percent putrescine composition. The test was doubleblind. The results obtained are summarized in Table 4. TABLE 4 Durationof Relief 2 Percent Duration of Relief Subject Myoflex Ranking (Hours)Putrescine (Hours) 1 3 1-3 4  2-12 2 1-2 2 3-4 5-6 3 1 2 3 4-6

[0073] A useful embodiment of the invention is one in which lidocaine isincorporated into a topical composition: Component Percent by Weightdeionized water 63.95 urea 10.00 N-propyl alcohol 7.00 carbowax PEG-4005.00 triethanolamine 4.75 lidocaine 4.00 putrescine 2.00 lechithin 1.00oleic acid 1.00 carbomer 940 0.40 imidazolidinyl urea 0.30 allantion0.20 methyl paraben 0.20 tetradecyl trimethylammonium bromide(Cetrimide) 0.20

[0074] While in this specification the invention has been described indetail through an example of some of the preferred embodiments thereof,it will be obvious to a person skilled in the art that many variationsand modifications could be made without departing from the scope andspirit of the present invention. Therefore, the present invention shouldbe considered as limited only by the scope.

[0075] All patents and publications referenced to throughout thespecification are hereby incorporated in their entirety as though thecontents thereof had been reproduced herein, without admission that suchis prior art.

1. A method for producing local analgesia in a subject having a site oflocal discomfort, the method comprising topically administering aneffective amount of an aliphatic polyamine to the site.
 2. A method forproducing relief in a subject having a site subject of nociceptivestimulation, the method comprising topically administering an effectiveamount of an aliphatic polyamine to the site.
 3. The method of claim 1or 2, wherein the polyamine is an alkylamine, preferably in which all ofthe amines a primary alkyl amines.
 4. The method of claim 1, 2 or 3,wherein the polyamine has up to fifteen carbon atoms.
 5. The method ofany of claims 1 to 4, wherein the polyamine has up to four amino groups.6. The method of any of claims 1 to 4, wherein the polyamine has up tothree amino groups.
 7. The method of any of claims 1 to 6, wherein thepolyamine is saturated.
 8. The method of any of claims 1 to 7, whereinthe polyamine is non-cyclic.
 9. The method of any of claims 1 to 8,wherein the polyamine has up to ten carbon atoms.
 10. The method ofclaim 9, wherein the polyamine is spermine.
 11. The method of claim 9,wherein the polyamine has at least four carbon atoms.
 12. The method ofclaim 11, wherein the polyamine has up to seven carbon atoms.
 13. Themethod of claim 12, wherein the polyamine is putrescine.
 14. The methodof claim 12, wherein the polyamine is spermidine.
 15. The method ofclaim 12, wherein the polyamine is cadaverine.
 16. The method of anypreceding claim wherein the polyamine is administered as part of acomposition and wherein the polyamine may be present, at least in part,as a pharmaceutically acceptable salt.
 17. The method of claim 16,wherein the polyamine makes up between 0.1 and 10 weight percent of thecomposition administered to the site, or between 0.2 and 9 percent, orbetween 0.3 and 8 percent, or between 0.4 and 7 percent, or between 0.5and 6 percent, or between 0.6 and 5 percent, or between 0.7 and 5percent, or between 0.8 and 5 percent, or between 1 and 4 percent orbetween 1 and 3 percent, or between 1 and 2 percent.
 18. The method ofany preceding claim, wherein the site is located on the epidermis of ahuman.
 19. The method of any of claims 16 to 18, wherein the compositionfurther comprises a chaotropic agent.
 20. The method of claim 19,wherein the chaotropic agent is urea, or is oleic acid, or is acombination of urea and oleic acid.
 21. The method of claim 20, whereinthe urea makes up about, or at least 5 percent, or about or at least 10percent, or about at least 15 percent, or about or at least 20 percent,or about or at least 25 percent, or about or at least 30 percent, orabout or at least 35 percent, or about or at least 40 percent, byweight, of the composition.
 22. The method of any of claims 16 to 21,wherein the composition includes a pharmaceutically acceptable vehiclecompatible with mammalian skin, and particularly, human skin.
 23. Themethod of any of claims 16 to 22, wherein composition is a cream, or ais a spray, or is an ointment or is a gel, or is a lotion.
 24. Themethod of any of claims 16 to 23, wherein the composition furthercomprises beta 1,3-D glucan.
 25. The method of any of claims 16 to 24,wherein the composition further comprises lidocaine.
 26. The method ofany preceding claim, wherein the discomfort is the result of a sportsinjury, a physical assault, arthritis, rheumatism, headache, shingles,surgical pain, or a combination of any of the foregoing.
 27. The methodof any of claims 1 to 25, wherein the pain being experienced by themammal is the result of a non-pathological condition.
 28. The method ofany of claims 1 to 25, wherein the subject is suffering fromfibromyalgia.
 29. The method of any of claims 1 to 22, whereinadministering the polyamine includes mounting a patch having thepolyamine incorporated thereinto at the site such that the polyamine istransferred from the patch to the site.
 30. The method of claim 29,wherein release of the polyamine from the patch is controlled to producethe analgesia over a period of time, wherein the period of time can beup to about one week, or wherein the period of time is between about onehour and one week, or between one hour and six days, or between sixhours and five days, or between six hours and four days, or betweentwenty-four hours and three days, or between one day and two days. 31.The method of any preceding claim, wherein the site is free ofextracellular wound scar skin tissue.
 32. The method of any of claims 1to 30, wherein the site is free of a wound undergoing healing of theskin.
 33. A topical analgesic drug composition comprising ananalgesia-inducing amount of at least one aliphatic polyamine and urea,wherein the urea is present in the amount of at least about 5, or about10, or about 15 percent urea, or about 20 percent urea, or about 25percent urea, or about 30 percent urea, or about 35 percent urea, orabout 40 percent urea.
 34. A topical analgesic drug compositionaccording to claim 32, and further according to any of claims 3 to 17,and any combination of the elements defined therein.
 35. A topicalanalgesic drug composition according to 33 or 34, and further comprisinga pharmaceutically acceptable vehicle compatible with mammalian skin,and particularly, human skin.
 36. A topical analgesic drug compositionaccording to any of claims 33 to 35, wherein composition is a cream, ora is a spray, or is an ointment or is a gel, or is a lotion.
 37. Atopical analgesic drug composition according to any of claims 33 to 36,wherein the composition further comprises beta 1,3-D glucan.
 38. Atopical analgesic drug composition according to any of claims 33 to 37,wherein the composition further comprises lidocaine
 39. A topicalanalgesic drug composition according to any of claims 33, 34, 35, 37 and38, wherein the polyamine is incorporated into a patch.
 40. Use of acomposition of any of claims 33 to 39 in the treatment of a subjecthaving a site of local discomfort.
 41. Use of a composition of any ofclaims 33 to 38 in the production of a medicament for the treatment of asubject having a site of local discomfort and/or subject having a sitesubject of nociceptive stimulation.